Foods That Reduce Inflammation

Organic Health Protocol

This eBook from professional trainer and nutritionist Thomas DeLauer and Dr. Mike Brookins shows you all of the secrets to reducing inflammation all through your body. These body hacks are secrets to the way that your body works that you would never have thought of. You will learn the foods that you will need to avoid in order to have a really healthy life. You will learn to reset your body in 7 days or less just by eating organic, really healthy foods. Food affects they way that your body works so much more than people tend to believe. You will learn how to cut through all the nonsense that you will read on the internet and get right to the part that heals your inflammation and other health problems. Inflammation is only a symptom If you are not healthy and eating well, your whole body will suffer. We give you a way to reverse that! Read more...

Organic Health Protocol Summary

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Author: Thomas DeLauer
Official Website: organichealthprotocol.com

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Recently several visitors of websites have asked me about this manual, which is being promoted quite widely across the Internet. So I bought a copy myself to figure out what all the excitement was about.

All the modules inside this book are very detailed and explanatory, there is nothing as comprehensive as this guide.

Nonopioids paracetamol combinations and nonsteroidal antiinflammatory drugs

Effective relief can be achieved with oral non-opioids and non-steroidal anti-inflammatory drugs (NSAIDs). These drugs are appropriate for many post-surgical and post-traumatic pains, especially when patients go home on the day of their operation. Figure 4.2 shows the evolving league table for analgesic efficacy compiled from randomised trials after all kinds of surgery. Analgesic efficacy is expressed as the number needed to treat (NNT) - the number of patients who need to receive the active drug for one to achieve at least 50 relief of pain compared with placebo over a six-hour treatment period. The most effective drugs have a low NNT of just over 2, meaning that for every two patients who receive the drug, one patient will get at least 50 relief because of the treatment (the other patient may obtain relief but it does not reach the 50 level). For

Carriers with Intrinsic Antiinflammatory Activity

Another approach to drug targeting is the use of carriers with an intrinsic pharmacological activity. In this 'dual targeting' strategy a beneficial effect is achieved both from the carrier itself and the drug it carries. The negatively-charged HSA carriers, for instance, developed for the targeting of drugs to HIV-infected cells, exert strong antiviral activity themselves 111 . Possible carriers with intrinsic anti-inflammatory activity are superoxide dismutase (SOD) and alkaline phosphatase (AP). AP is a membrane-anchored protein, that can be shed into the general circulation, which was shown to be able to detoxify LPS in vivo through dephosphorylation 114 .This dephos-phorylating activity could be enhanced by increasing the negative charge of the enzyme through succinylation 115 . Using AP as a carrier for anti-inflammatory drugs to KCs, the main site of LPS uptake, it could intrinsically contribute to therapeutic efficacy in cirrhosis through detoxicification of LPS. The...

The Nonsteroidal Antiinflammatory Drug

The ideal NSAID agent has not yet been developed. Efforts have been continuous since the introduction of aspirin in 1899. For example, the patent literature for 1966 alone reveals disclosures of more than 100 groups (not single compounds) of antiinflammatory structures. The pace of research is not likely to have abated. Unfortunately, only a small number of lead compounds emerge with sufficient potency and adequate tolerance for further development. Chronic toxicity determinations in animals further reduce the number of agents reaching even the preclinical stages of testing. The saga of the search for a better aspirin is particularly illustrative of the rationale involved and the problems encountered. The goal of a highly potent long-acting variant of aspirin with low toxicity has been pursued in both industrial and academic institutions. A long systematic study to determine the optimum structure-activity relationships of salicylates was undertaken to find the best candidate from over...

Targeting of Antiinflammatory Drugs for the Treatment of Liver Fibrosis

As described above there are several carriers available for targeting the key cells in the hepatic inflammatory process. The method of loading a carrier with anti-inflammatory drugs largely depends on the proposed entry mechanism of the carrier into the cell. Most drugs are not active when coupled to albumin or incorporated in liposomes and have to be released from the carrier first. Ideally, the carrier should be stable enough in the bloodstream for the drug to be released only within the target cell. In the case of drug-filled liposomes and drug molecules covalently linked to albumin this means the carrier must be degraded in the target cell for the drug to be released. Most of the receptors described above which are responsible for the uptake of carriers are linked to a lysosomal degradation route. After receptor-mediated uptake most of the carrier is thus lysosomally degraded and a pharmacologically active drug can be released. For covalently attached drugs this means enzymatic...

Antiinflammatory activity

The anti-inflammatory effect of fucoxanthin is mainly based on modulation of macrophages function. Macrophages are the residents of immune cells in the innate immune system which play an important role in the maintenance of homeostasis by changing their function according to the tissue. As the residence of the immune system, macrophages are a predominant source of proinflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), proinflammatory cytokines tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and interleukin-1 (IL-1 ) , and ROS (Block et al., 2007). It has been consistently demonstrated that the origin of cancer was at sites of chronic inflammation, in part based on the hypothesis that some classes of irritants, together with the tissue injury and ensuing inflammation they cause, enhance proliferation. Chronic inflammation may also play significant role in mediating neurodegenera-tive diseases such as Parkinson's disease (PD), AD, multiple sclerosis (MS),...

Anti Inflammatory Effect

Attenuate neutrophil infiltration into the inflammatory site and may be a novel tool for the regulation of inflammation (Fig. 5). The signal transduction mechanism of extracellular TRX is now under investigation. Since TRX is a 12 kDa protein, it is unlikely that TRX itself goes through the cell membrane. Our data showing that the redox-inactive mutant TRX does not show the extracellular cytoprotective or antiinflammatory effect suggest that the active site of TRX is important for the signal transduction of extracellular effect of TRX. The disulfide-dithiol exchange between extracellular TRX and possible target protein on the cell surface may be involved in the signal transduction. The study is ongoing to identify the possible target molecules for extracellular TRX (Fig. 6).

Nonsteroidal Antiinflammatory Drugs

All NSAIDs, including the traditional nonselective drugs and the subclass of selective cyclooxygenase-2 (COX-2) inhibitors, are anti-inflammatory, analgesic, and antipyretic. NSAIDs are a chemically heterogeneous group of organic acids that share certain therapeutic actions and adverse effects. Aspirin also inhibits the COX enzymes but in a manner molecularly distinct from the competitive, reversible, active site inhibitors and is often distinguished from the NSAIDs. Similarly, acetaminophen, which is antipyretic and analgesic but largely devoid of anti-inflammatory activity, also is conventionally segregated from the group despite its sharing NSAID activity with other actions relevant to its clinical action in vivo.

Concurrent Use ofInhaled Long Acting b2Adrenoceptor Agonists and Topical Antiinflammatory Glucocorticoids in Asthma

The reason why chronic asthma should be treated by concurrent inhalation of a b2-agonist, such as salmeterol, and a topical anti-inflammatory steroid is that their inhibitory actions on the inflammatory cells involved are complementary and their therapeutic effects are synergistic. The cellular basis for this approach is summarized in Table 11. The effects of b2-agonists on these cells have already been outlined in Section II. The complexity of the actions of glucocorticoids on them is well summarized in Taylor and Shaw's review (59). Table 11 Complementary Actions of b2-Adrenoceptor Stimulants and Antiinflammatory Steroids on Cells Involved in the Pathology of Asthma Activation inhibited by antiinflammatory steroidsa a Anti-inflammatory steroids also reduce the number of proinflammatory cells by inhibiting their replication and their migration into the bronchial mucosa and by inducing death by apoptosis.

The Prostaglandins And Nonsteroidal Antiinflammatory Agents

Aspirin 5.14 is the best known of a family of drugs that are known as the non-steroidal anti-inflammatory drugs (NSAIDs). These drugs are used because of their analgesic (pain-killing), anti-inflammatory and anti-pyretic (fever reducing) properties. Aspirin has its origins in folk medicine. Chewing the bark of the willow tree (Salix europea) alleviated pain associated with rheumatism, toothache and headache. Salicin 5.15 and salicylic acid 5.16 were originally isolated from this source. They were used in the nineteenth century for the treatment of rheumatic fever and for their anti-pyretic and anti-inflammatory properties. Salicylic acid became readily available from phenol 5.17 by the Kolbe reaction. However, it produced side effects involving gastrointestinal damage. It was found that acetylation reduced these side effects and aspirin was introduced in 1899. Other salicylates derived from natural sources have useful anti-inflammatory action. Oil of wintergreen (methyl salicylate) is...

Antiinflammatory lipid analogs derived from damino acids

More than 100 human inflammatory conditions are now known to be mediated by the same networks of endogenous proteins, with numerous built-in redundancies and feedback regulatory mechanisms that continue to confound our understanding of disease progression.20 Most antiinflammatory drugs available for use in humans are non-steroidal antiinflammatory drugs (NSAIDs) that typically block formation or action of inflammatory mediators (e.g., prostaglandins, leukotrienes, thromboxanes, platelet activating factor) produced near the bottom of the inflammatory cascade from arachidonic acid. The latter is produced via the degradation of membrane phospholipids, which is particularly accelerated after activation of macrophages in response to inflammatory stimuli (e.g., bacteria, viruses, parasites, endotoxins, autoantigens) and release of proinflammatory cytokines (e.g., TNFa, IL-1, IL-6, etc.), which in turn cause secretion of enzymes known as phospholipases A2 (PLA2).21-25 This family of...

Mode of Anti Inflammatory Actions of Aspirin

Among the multiple pharmacological actions of aspirin, most of the attention has been focused on its analgesic anti-inflammatory effects. This was also the reason why the substance was originally developed and clinically introduced (Section 1.1.3). Originally, it was thought that the anti-inflammatory action of aspirin (and salicylate) might result from its effects on cellular energy metabolism, that is, uncoupling of oxidative phosphorylation. This hypothesis, although attractive, was rejected 333 (Section 2.2.3). Future research was focused to more specific actions of salicylates on cells of interest. This included white cells, their numerous activation and secretion products, and the vascular endothelium. Aspirin appears to be a more potent inhibitor of COX-2-derived PGE2 formation in cell culture in vitro than its metabolite salicylic acid while activated salicylic acid (salicylyl-CoA) was active 334 . Other investigators obtained different results with different models 97 ,...

Antiinflammatory And Antirheumatic Drugs

NSAIDs are believed to exert their anti-inflammatory action primarily by the inhibition of the biosynthesis of prostaglandins and related cyclooxygenase-derived products. NSAIDs can also interfere with free radical generation and by trapping reactive free radical species (Arrigoni-Martelli, 1985). Indo-methacin (601), diclofenac (602), mefenamic acid (603), flufenamic acid (604), phenylbutazone (605), oxyphenbutazone (606) and acetylsalicylic acid (607) have been evaluated as inhibitors of the generation, or the activity, of oxygen free radicals in various assays. In one system where superoxide anion was generated by guinea-pig macrophages elicited by reaction with nicotinamide adenine nucleotide, diclofenac exhibited inhibition at 0.4 u-M, acetylsalicylic acid at 100 xm and the other drugs in the range in between.

Antiinflammatory Agents And Antioxidants In Cancer Chemoprevention

COX-2 inhibitors and other anti-inflammatory agents Other compounds, such as the natural product curcumin, are blockers of activation or transcription activity of the transcriptional factor nuclear factor-kB (NF-kB) (see Section 6.4 of Chapter 9), and have both anti-inflammatory and anticarcinogenic activity. Clinical trials of these compounds as chemopreventive agents were planned. However, suppression of NF-kB activity can increase susceptibility to infections.23

Miscellaneous Immunosuppressant And Antiinflammatory Agents

Dapsone (4,4'-diaminodiphenylsulfone) is used in dermatology for its anti-inflammatory properties, particularly in sterile (noninfectious) pustular diseases of the skin. Dapsone prevents the respiratory burst from myeloperoxidase, suppresses neutrophil migration by blocking integrin-mediated adherence, inhibits adherence of antibodies to neutrophils, and decreases the release of eicosanoids and blocks their inflammatory effects all these actions are likely to be important in autoimmune skin diseases. Thalidomide (thalomid) is an anti-inflammatory, immunomodulating, antiangiogenic agent (see Figure 51-6) that also can increase keratinocyte migration and proliferation.

Antioxidants and antiinflammatory agents

Reactive oxygen species (ROS) are involved in many biological processes including the inflammatory response. ' ' Ebselen (1) is an anti-oxidant and anti-inflammatory that has undergone Phase III clinical trials as a neuroprotective agent and is soon to become the first synthetic organoselenium therapeutic released on the market. Selenium is not liberated from Ebselen 1, and as such it is relatively non-toxic. The anti-inflammatory action of Ebselen 1 is attributed to its ability to interfere with a number of pathways to inflammation, either through its anti-oxidant capacity or through direct inhibition of enzymes.1,72,73 The role of hydroperoxides in inflammation is well known. Hydroperoxides are essential for the activation of inflammatory enzymes known as the lipoxygenases (LOX) and cyclooxygenases (COX).17,87 Of the lipoxygenases, 5-LOX is considered to be critical to inflammation as it catalyses the biosynthesis of pro-inflammatory leukotrienes from arachidonic acid.88 LOX and COX...

Antiinflammatory cytokinebased gene therapy in experimental autoimmune encephalomyelitis

To date, gene therapy has never been attempted in MS patients. Some experiments, mainly based on anti-inflammatory cytokine gene delivery, have been performed in animals affected by experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Gene therapy approaches so far attempted in EAE can be divided into two distinct categories (1) cytokine genes incorporated into viral vectors or plasmids and injected into the bloodstream or into circulating encephalitogenic T-cells and (2) cytokine genes transferred directly into the CNS using viral vectors, plasmids or engineered cell lines. Here is a brief summary of the results obtained.

Prostaglandins and Aspirin

Interspersed among this work on prostaglandin biosynthesis was another landmark discovery the demonstration, by Vane (22) and his colleagues, that this enzyme was the target for the aspirinlike drugs (non-steroidal anti-inflammatory drugs NSAIDs). At a stroke, this transformed our understanding of the pharmacology of these compounds but also provided prostaglandin researchers with a useful set of tools to explore further the biology of the prostaglandins. It also threw into sharp focus the importance of understanding the enzymology of the cyclo-oxygenase. Over the next couple of years, it was shown that the entire gamut of NSAIDs inhibited Cox at concentrations well within their therapeutic plasma range and that the overall order of potency corresponded with their therapeutic activity. Other types of anti-inflammatories, such as the glucocorticoids and the so-called disease modifying drugs such as gold and penicillamine, were inactive in these cell-free assays, providing further...

Derek W Gilroy Melanie Stables and Justine Newson Abstract

Inflammation is a primordial response that protects against injury and infection with the ultimate aim of restoring damaged tissue to its normal physiological functioning state. In fact, our well-being and survival depends upon its efficiency and carefully balanced control and to which we are alerted in the form of pain, swelling, and redness. Prostaglandins (PG), lipids derived from arachidonic acid metabolism by the enzyme cyclooxygenase, are historically one of the most well-studied mediators of the acute inflammatory response so much so that their inhibition by so-called non-steroidal anti-inflammatory drugs (NSAIDs) has been the mainstay for the treatment of diseases where inflammation becomes a pathological driving force. However, while NSAIDs relieve the symptoms of dyregulated inflammatory responses, they do not cure the underlying disease and have associated gastrointestinal and renal toxicity. These side effects arose from inhibiting constitutively expressed, protective...

COX2 Inhibition in Inflammation

While COX-2 is highly up-regulated in artificially-stimulated cell culture as well as in intact tissues during infection and injury, COX-1 is also expressed in this setting. The prevailing question at the time asked what the relative expression and temporal profile of COX-1 versus COX-2 through the time course of an experimental inflammation. Moreover, what was the respective contribution of COX-1 versus COX-2 to pathogenic eicosanoid generation responsible for disease symptoms Remember, central to the selective COX-2 inhibitor idea is the assumption that COX-2 is solely responsible for the production of PGs at sites of inflammation. Thus, if COX-1 contributes significantly to the production of PGs, selective blockade of COX-2 will not produce anti-inflammatory effects to the same extent as drugs that inhibit both isoforms. Arising from a flurry of investigation firstly in vitro, then in rodents and finally in man, COX-2 was indeed expressed at sites of inflammation making abundant PG...

The Cox1 Cox2 Concept

Most of the biological data suggested that Cox-2 was the predominant inflammatory species, and by implication, the best target for NSAIDs. So was Cox-2 inhibition the true therapeutic modality of NSAIDs If so, Cox-1 inhibition might account for the side effects, such as gastric irritation and depression of platelet aggregation. This was the notion advanced by more than one group (26, 27) which came to be known as the Cox-2-bad Cox-1-good hypothesis. If true, then the obvious corollary was that a selective Cox-2 inhibitor should be an ideal drug, possessing anti-inflammatory actions but lacking gastric and other side effects. The culmination of this, and many other similar studies, was the launch, in the 1990s, of celecoxib, rofecoxib, and subsequently other selective Cox-2 inhibitors. The therapeutic history of this field has not been entirely happy, but there is no doubt that it remains an influential concept. It is generally accepted that the anti-inflammatory action (and probably...

COX2 and Resolution

Studies on the other end of the inflammatory spectrum, resolution, have revealed a hitherto unappreciated role for COX-2 as well as COX-2 lipoxygenase interaction products (epi-lipoxins, resolvins, etc.) in controlling the severity of inflammation and its longevity. For instance, PGD2 has emerged recently as an eicosanoid with both pro- as well as anti-inflammatory properties. PGD2 undergoes dehydration in vivo and in vitro to yield biologically active PGs of the J2 series, including PGJ2, A12, 14-PGJ2 and 15-deoxy-A12, 14-PGJ2 (15d-PGJ2). In addition to being a high-affinity natural ligand for anti-inflammatory peroxisome proliferators-activated receptor gamma (PPARg), 15d-PGJ2 also exerts its effects through PPARg-dependent as well as -independent mechanisms to suppress pro-inflammatory signalling pathways and the expression of genes that drive the inflammatory response (13). We have shown that COX-2-derived PGD2 metabolites contribute to the resolution of acute inflammation...

Prostanoids

Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P (2003) The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A 100 9108-9110

Pulmonary Drug Delivery Delivery to and Through the Lung

4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Endothelial and Kupffer Cells for the Treatment of Inflammatory Liver Diseases 4.5.1.3 Carriers with Intrinsic Anti-inflammatory Activity 102 4.6 Anti-inflammatory Drugs 4.6.1 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 103 4.6.3 Other Anti-inflammatory 4.9 Targeting of Anti-inflammatory Drugs for the Treatment of Liver Fibrosis . . 110

Essential Fatty Acids

An important step forward in the development of eicosanoid research was the discovery of the prostaglandin endoperoxides PGG2 and PGH2 18,19 , In the beginning, these intermediates of enzymatic prostaglandin synthesis were thought to be identical with so-called rabbit aorta-contracting substance (RCS) 20 and labile (platelet) aggregation-stimulating substance (LASS) 21 . Both were found in pharmacological experiments as short-lived activities which were released, for instance, from allergen-challenged guinea-pig lung. Later on, thromboxane A2 was identified as the major component of RCS and LASS 22 . At about the same time, the Vane and his collegues. 23 postulated the existence of an endogenous thromboxane A2 antagonist, 'PGX', which was then characterized as PGI2 or prostacyclin. Vane 24 and another group 25 made the most important and remarkable discovery that cyclooxygenase, i.e. the enzyme controlling the initial step of prostaglandin, thromboxane and prostacyclin biosynthesis,...

The Transacylationphosphodiesterase

Ethanolamides of long-chain fatty acids, referred to as N-acylethanol-amines (NAEs), comprise several bioactive compounds such as N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine, and N-oleoylethanolamine. Anandamide was most extensively investigated (Di Marzo, 1998 Pacher ei a ., 2006) since the discovery in 1992 as the first endocannabinoid (endogenous ligand of cannabinoid receptors) (Devane ei a ., 1992). On the other hand, N-palmitoylethanolamine and N-oleoyl-ethanolamine, which are insensitive to cannabinoid receptors, receive considerable attention due to anti-inflammatory and analgesic activities (Lambert ei a ., 2002) and anorexic activity (Rodriguez de Fonseca ei a ., 2001), respectively. Recent studies suggest involvement of the nuclear receptor PPAR-a (LoVerme ei a ., 2005) and G-protein-coupled receptor GPR-119 (Overton ei a ., 2006) in signal transduction by these NAEs.

Introduction to Green Chemistry Organic Synthesis and Pharmaceuticals

The well-being of modern society is unimaginable without the myriad products of industrial organic synthesis. Our quality of life is strongly dependent on, inter alia, the products of the pharmaceutical industry, such as antibiotics for combating disease and analgesics or anti-inflammatory drugs for relieving pain. The origins of this industry date back to 1935, when Domagk discovered the antibacterial properties of the red dye, prontosil, the prototype of a range of sulfa drugs that quickly found their way into medical practice.

Confounding by indication

Bias arises in observational studies when patients with the worst prognosis are allocated preferentially to a particular treatment. These patients are likely to be systematically different from those not treated or treated with something else (paracetamol rather than nonsteroidal anti-inflammatory drugs (NSAID) in asthma, for instance).

Potential Mechanisms Of Suppressing Brain Macrophage Functions

Astrocyte-derived factors have been observed to downregulate MHC class II molecules on macrophages.3 This may be a mechanism to inhibit the APC function of microglia. Neutralization of TGF-p eliminates the downregulatory effect, suggesting that TGF-p immunosuppresses activated microglia.61 Both TGF-p and TGF-p2 inhibit endotoxin-induced NO production by rat microglia.62 Antibodies against TGF-p enhance the clinical severity of EAE.63 It is proposed that TGF-p is induced during the reactive inflammatory phase of disease and then exerts anti-inflammatory effects in the brain. TGF-p has been shown to suppress the release of oxygen free radicals by cultured macrophages64 and to selectively induce microglial apoptosis.65 TGF-p is therefore a powerful candidate suppressor molecule, as it appears to mediate its inhibitory effects on a spectrum of microglial functions. IL-10 is another anti-inflammatory cytokine. Elevated expression of IL-10 has been observed in brains of mice during the...

Boron Compounds as Therapeutic Drugs

Boron analogues of nucleosides, nucleotides, amino acids and nucleic acids possess potent anti-cancer,11 13 anti-inflammatory,14 hypolipidaemic and anti-osteoporotic15 properties. The primary focus of this chapter is on the applications of boronated compounds for boron neutron capture therapy (BNCT).

Pharmacodynamic Interactions

The oral anticoagulant warfarin has a narrow margin between therapeutic inhibition of clot formation and bleeding complications and is subject to several important drug interactions (see Chapter 54). Nonsteroidal anti-inflammatory drugs cause gastric and duodenal ulcers (see Chapter 36), and their concurrent administration with warfarin increases the risk of GI bleeding almost fourfold compared with warfarin alone. By inhibiting platelet aggregation, aspirin increases the incidence of bleeding in warfarin-treated patients. Finally, antibiotics that alter the intestinal flora reduce the bacterial synthesis of vitamin K, thereby enhancing the effect of warfarin. A subset of nonsteroidal anti-inflammatory drugs, including indomethacin, ibuprofen, piroxi-cam, and the cyclooxygenase (COX)-2 inhibitors, can antagonize antihypertensive therapy, especially with regimens employing angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and b adrenergic receptor antagonists....

Aging and Muscle Action

Increased ROS can contribute to sacropenia, cell damage and death via two distinct processes apoptosis and necrosis. Apoptosis is a type of programmed cell death where cells follow an orderly series of self-destructive events that include cell shrinkage, cell bubbling, and the breakdown of DNA, protein, mitochondria, and cell membrane. The damaged cell membrane attracts phagoyctic cells that engulf the damaged cell membrane fragments and secrete anti-inflammatory cytokines such as IL-10 and TGF-5. This is a very different process than necrosis. Necrosis is the death of cells in a tissue usually caused by an injury. Necrosis can be caused by an exercise-induced mechanical or metabolic attack on the cell. As a result of the attack, osmotic pressure and swelling increases inside the cell to a bursting point after which the cell contents actually spill out through ruptures in the membrane. The outpouring of the cell's contents and pro-inflammatory cytokines (e.g. tumor necrosis factor...

Neurochemicals in Pain Processing

A number of neurotransmitters and chemical substrates are involved in pain transmission several are listed in Table 2-2. For example, in the periphery, tissue injury results in the activation of a number of cellular processes that release chemical compounds that can activate free nerve endings for pain transmission (Snyder 1980), such as acetylcholine, bradykinin, histamine, potassium ion, and serotonin (Levine et al. 1993). Additional agents that are active within the CNS are also listed in Table 2-2. Some of these substances have a pain-promoting role, whereas others have a pain inhibitory role. Many of these substances are the targets of influence when analgesics are employed (e.g., antiinflammatory agents and antidepressants), as is described further in Chapter 5, Pharmacology of Pain, of this book.

Matrix Metalloproteinases

This was paralleled by restoration of the damaged BBB in the inflammatory phase of the disease, and a significant reduction in MMP-9 activity within the CSF. However, no change in the degree of inflammation and demyelination was noted.77-78 In a delayed-type hypersensitivity, non-CNS antigen, rodent model of MS that causes focal demyelinating lesions morphologically similar to MS plaques, MMP inhibition was able to prevent both inflammation and demyelination.79 In chronic relapsing EAE, a synthetic MMP inhibitor was shown to completely block acute and to reverse established severe disease. In this study, mRNAs for TNF-a and the cell death signaling molecule FasL were found to be downregulated, whereas mRNA for the anti-inflammatory Th2 cytokine IL-4 was upregulated.80

Alternative Therapeutic Targets in Pain Therapy

Another therapeutic target is adenosine kinase. Via activation of adenosine receptors nociceptive, sensory input is modulated. Adenosine kinase phosphorylates adenosine and maintains low intracellular levels of this neurotransmitter. Adenosine kinase inhibitors (e.g. GP515, GP3269, A-134974 and ABT-702) increase the endogenous levels of adenosine and have been shown to elicit analgesic and anti-inflammatory effects in several animal models. These effects appear to be due to enhanced adenosine receptor activation since they are blocked by adenosine receptor antagonists.

Stereoselectivity in Drug Disposition

Enantioselective tissue binding, which is in part a consequence of enantioselective plasma protein binding, has been reported. For example, the transport of the arylpropionic non-steroidal anti-inflammatory drug (NSAID) ibuprofen into both synovial and blister fluids is preferential for (S)-ibuprofen owing to the higher free fraction of this enantiomer in plasma (Seideman et al., 1994). In addition the affinity of stereoisomers for binding sites in

An Overview Of Metabolic Syndrome A Precursor Of Diabetes Heart Disease And Stroke

Adipose cells function not only as energy storage vessels but also as sources of regulatory molecules. One such regulator is the small protein leptin, which after secretion by fatty tissue travels to the brain where it normally induces a signal to decrease food intake. Another regulator is adiponectin, which increases insulin sensitivity, decreases glucose production in the liver, and increases glucose uptake by the muscle, all of which are antidiabetic activities. Adiponectin also decreases circulatory lipid and cholesterol and is anti-inflammatory. Excess body fat (especially abdominal fat) is associated with deregulation and abnormal function, including diminished adiponectin secretion and increased production of the proinflammatory TNF-a. The dysfunctional behavior of adipocytes in excessively heavy or obese individuals may be a consequence of several factors, including inflammation due to macrophage infiltration, cumulative damage by reactive chemical fragments and disregulation...

Pain Augmenting Mechanisms and the Emergence of Chronic Pain

Ongoing abnormalities in peripheral tissues, with resultant inflammation, can result in activation of nociceptive pathways, rendering pain chronic. In such cases, treatment is best directed at the inflammatory mechanisms (e.g., aspirin or nonsteroidal anti-inflammatory agents). Peripheral nerves may become dysfunctional due to injury or disease (e.g., diabetes, infection, toxin exposure). Damaged neurons may fire spontaneously. Nociceptive fibers firing in this way are perceived in the CNS as signaling pain, yet in the peripheral tissues there may be no current injury. In such cases, antidepressants and anti-convulsants might be the most helpful treatment.

Adjuvant Analgesics In Pain Therapy

Adjuvant analgesics are compounds that are not classified as analgesics, but are used clinically for the relief of pain. This class of analgesics contains a wide range of compounds that belong to a variety of chemical families. They are classified according to their use and their mechanisms of action are often not well defined. For example, antidepressants are used to control neuropathic pain, a2-adrenoceptor agonists (e.g. clonidine, dexmedetomidine) potentiate the anti-inflammatory and analgesic effects of COX inhibitors, while corticosteroids block inflammation and may directly modulate the nociceptive action of substance P. Compounds that have been especially beneficial in the treatment of neuropathic and phantom limb pain include local anesthetics (e.g., mexiletine, flecainide), anticonvulsants (gabapentin, carbamazepine, phenytoin, valproate, clonazepam, lamotrigine), GABA agonists, neuroleptics and calcitonin. Other analgesics such as muscle relaxants and benzo-diazepines are...

Targeting Microgliosis

Activation of microglia surrounding amyloid plaques in AD brains could be a double-edged sword. On one hand, activated microglia can release harmful inflammatory substances. On the other hand, activated microglia can scavenge toxic Aft. Microglial activation can be inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Epidemiological studies show that NSAID usage is associated with a lower risk of AD 134 . However, clinical trials of NSAIDs in AD patients have been largely disappointing 134 . The lack of efficacy of NSAIDs can be ascribed to its potential use only for prevention but not treatment, the inappropriate doses or drugs chosen in the trials or a faulty hypothesis. In contrast to NSAIDs, Aft immunotherapy may depend at least in part on the activation of microglia 34 . Aft immunotherapy is currently being investigated in clinical trials (Tables 1 and 2). It has been proposed that there maybe multiple activation states of microglia some could be associated with release...

Neuroprotective Agents

Large doses of tBuOOH (110 mg kg, ICV) induce a largely necrotic lesion that results in 94 mortality within 24 h. Most mice die within 4 h. A number of compounds were tested and found to not increase survival following tBuOOH-induced necrosis. These agents include -acetylcysteine used as an antioxidant (160 mg kg, 15 min prior to tBuOOH), the calcium channel blocker nifedipine (0.4 mg kg, 20 min prior to tBuOOH), the antioxidant vitamin C (100 mg kg, 30 min prior to tBuOOH), the antioxidant GM1 ganglioside (30 mg kg, 20 min prior to tBuOOH), and the anti-inflammatory steroid 6-a methylprednisolone (30 mg kg, 20 min prior to tBuOOH).

Managing Chronic Pain Using Nonopioid Medications

Tie mainstay for treating chronic pain is medication management. Most patients expect to receive a medication prescription when they see their primary care provider with a pain complaint. However, for some conditions, such as low back pain, the current recommendations for the acute phase is acetaminophen nonsteroidal anti-inflammatory drugs (NSAIDs) and continued activity, rather than opioids and bed rest. About 15 of the patients who have acute low back pain progress to chronic low back pain. Medication management for chronic low back pain is recommended, accompanied by a plan of care that includes medications along with other therapies, such as physical therapy and counseling (D'Arcy, 2009b). Opioids are in most cases reserved for severe level pain that is impairing functionality.

Pharmacogenetics Moving From Research To The Clinic

It is anticipated that regulatory authorities will increasingly expect to see this type of application of scientific advances, such as pharmacogenetics, being employed in the assessment of new medicines. The FDA Critical Path White paper, issued 14 March 2004 entitled Innovation or stagnation Challenge & opportunity on the critical path to new medical products sets out this vision and expectation for clinical drug development. Regulatory authorities are under increasing public opinion scrutiny to understand safety risk, particularly in the wake of the recent voluntary withdrawal of the widely used pain-killer and anti-inflammatory inhibitor drug, Vioxx (rofecoxib) by Merck in September 2004 due to cardiovascular risk concerns. Pharmacogenetics is about assessing individuals and must be a core component of the strategy to explore safety signals of clinical concern observed in patients following drug administration. Regulatory authorities are likely to be a key driving force in...

Preliminary considerations

Although pro-inflammatory cytokines represent a suitable therapeutic target in MS, therapies based on the use of cytokines with an anti-inflammatory profile (IFN-p, IL-4, transforming growth factor (TGF)-p, IL-10) so far attempted in MS patients have been mostly disappointing. Subcutaneous as well as intramuscular administration of IFN-p in patients with relapsing-remitting MS is only partially effective7,8 since it reduces by one-third the disease exacerbation rate and does not change substantially the progression of disability. Systemic administration of TGF-p does not induce any change in the disability status of patients or in the appearance of brain magnetic resonance imaging lesions.9 Intravenous injection of the recombinant TNF receptor p55 immunoglobulin fusion protein Lenercept in MS patients induces an increase in the number of patients experiencing exacerbations.10

Pharmacological Properties Pharmacodynamics

Uric acid, discovered in 1776 by Scheele, is the basis for the 2,500 barbiturates synthesized over the years with antimicrobial, antitumor, spasmolytic, anticonvulsant, hypnotic-sedative, anti-inflammatory, analgesic, diuretic, or herbicidal properties. Those with past or current clinical applications are displayed in Table 1.

Fatty acid amide hydrolase AEA degradation and beyond

Possibility that another AEA hydrolysing enzyme may exist in peripheral organs should not be ruled out. This is unlikely to be the recently cloned W-acylethanolamine-hydrolysing acid amidase (Tsuboi et al. 2005), since this enzyme is specific for long-chain saturated W-acylethanolamines. Conversely, it is clearly emerging that FAAH is also involved in the control of fatty acid amides different from AEA. In a recent study (Cravatt et al. 2004), it was elegantly shown how the genetic inactivation of the Faah gene, when limited to peripheral tissues, resulted in an anti-inflammatory phenotype that was not due to elevated activation of CB1 receptors. The authors suggested that other bioactive fatty acid amides that are substrates for FAAH, i.e. oleoylethanolamide, palmitoylethanolamide or W-arachidonoyl-glycine, could be responsible for the elevated threshold to inflammatory pain via peripheral actions.

Glucocorticoids and inhibitors of their biosynthesis as antitumor agents

The immunosuppressive and anti-inflammatory activities of the glucocorticoids are well known. They exert an influence in human lymphoid tissue (e.g., they can modify the homing of lymphocytes into lymphoid organs), and for this reason they are often useful in the treatment in acute lymphoblastic leukemia and other chronic and acute leukemias. Prednisone is normally employed for this purpose, normally in association with other types of chemotherapy. Because of their anti-inflammatory action, corticosteroids are often included in antitumor regimens to alleviate cancer pain.49

Silica And Cell Death

It is believed that cell necrosis triggers inflammation but that apoptosis does not. Biochemical evidence suggests that necrotic cells release a number of intracellular lytic enzymes, mediators, cytokines, chemokines, and other proinflammatory factors that damage neighboring cells and elicit an inflammatory response. Recent studies by Scaffidi et al.112 indicate that the release of chromatin protein, such as high mobility group 1 (HMGB1) from necrotic cells, could serve as a major diffusible signal for inflammatory responses. In cells without the hmgbl gene, the induction of inflammation is less efficient. In contrast, the apoptotic cells were unable to induce inflammation due to the tight association of HMGB1 with hypoacetylated intact or fragmented chromatin. However, several recent studies document that apoptotic cells could also be involved in the regulation of inflammation.113 As discussed earlier, the apoptosis induced by silica might be through the Fas FasL system. The possible...

Mechanism of action and metabolism

Paracetamol is an effective analgesic with antipyretic but not anti-inflammatory activity.45 II The mechanism of its analgesic action is not fully understood, but has a central effect inhibiting COX.94 At therapeutic dosages, it does not inhibit COX in peripheral tissues, which explains its lack of anti-inflammatory activity.95 Recent research has shown the presence of a new COX enzyme, COX-3, found in the brain and spinal cord, which is selectively inhibited by paracetamol, and is distinct from the two already known COX enzymes COX-1 and COX-2. There are suggestions of selective inhibition of the enzyme COX-3 in the brain and spinal cord by paracetamol, which explains its effectiveness in relieving pain and reducing fever without having unwanted GI side effects.96 Other reports suggest a selective COX-2 inhibition97 (see Chapter 4, Clinical pharmacology traditional NSAIDs and selective COX-2 inhibitors in the Acute Pain volume of this series for a full description of its...

Chromatographic pKa Measurement

Oumada et al. 148 described a new chromatographic method for determining the aqueous pKa of drug compounds that are sparingly soluble in water. The method uses a rigorous intersolvent pH scale in a mobile phase consisting of a mixture of aqueous buffer and methanol. A glass electrode, previously standardized with common aqueous buffers, was used to measure pH online. The apparent ionization constants were corrected to a zero-cosolvent pH scale. Six sparingly soluble non-steroidal antiinflammatory weak acids (diclofenac, flurbiprofen, naproxen, ibu-profen, butibufen, fenbufen) were used successfully to illustrate the new technique.

Physical Properties

Basis of fucoxanthin, a pigment that is most efficient in utilizing the blue-green light that penetrates the ocean. And that is one good reason for the brown coloration of kelp. Presence of fucoxanthin adds to the biological properties of kelps (discussed later in this chapter) as it is medically interesting and is under investigation for anticancer and anti-inflammatory properties.

Early Experimental Data Implicating Neuroinflammatory Processes

The classical view of the brain as an immunologically privileged site primarily due to its effective selectivity and the relative impermeability of the blood-brain barrier has made it difficult to consider the notion that inflammatory processes, also classically considered to be a domain of the circulatory system, occur in the brain. But the early findings by the McGeer and Rogers groups, starting as early as 1987, on the expression of immune system antigens (16), the presence of reactive microglia (17), and the activation of the classical compliment pathway in Alzheimer's disease (AD) brain (18) strongly implicated neuroinflammatory processes. In addition, their early demonstrations that rheumatoid patients taking antiinflammatory drugs had delayed appearance of AD symptoms (19) also strongly suggested the importance of neuroinflammatory events in the dementia associated with the disease. The early demonstrations that proinflammatory cy-tokines were shown to be elevated in...

Regulation of the Inflammatory Process by SECs

Exposure of the SECs to pathogens or cytokines produced by other cells during stress induces activation of the SECs and subsequent production of cytokines, eicosanoids, and or adhesion molecules. For instance, after activation with LPS, a main component of the walls of gramnegative bacteria and a major inducer of inflammation and non-specific immune functions 20 , SECs produce a number of pro- and anti-inflammatory cytokines. Pro-inflammatory cytokines shown to be produced were tumour necrosis factor alpha (TNFa) 26 interleukin-1 alpha beta(IL-1a ) 27 the major inducer of acute phase proteins interleukin-6 (IL-6) 28 and the neutrophil chemo-attractant interleukin-8 (IL-8) 29 . Anti-inflammatory cytokines shown to be produced were interleukin-10 (IL-10) 27 and hepatocyte growth factor (HGF) 30 .

Hepatic Inflammation and Fibrosis

Since not every insult necessarily results in liver fibrosis, counter-regulatory mechanisms must also exist. During inflammation, elimination of ROS by SECs and KCs is enhanced via increased expression of radical scavengers like superoxide dismutases and glutathione per-oxidase. The radical nitric oxide itself also has an anti-inflammatory role. It has been described to prevent leucocyte adhesion to the endothelium 68 and to block an activation pathway of thrombocytes by stimulating guanylyl cyclase 69 . Furthermore, both PGE2 and IL-10 can downregulate cytokine production by macrophages 70,71 and can also inhibit the antigen-presenting properties of SECs and KCs 18,72 . HGF produced by KCs, SECs, and quiescent HSCs is a potent mitogen for PCs and stimulates liver regeneration. It is probably aided by PGE2 which also stimulates DNA synthesis in PCs 73 . Finally, scar tissue formation is not only regulated by production of extracellular matrix components, but also by the degradation of...

Inflammatory bowel disease IBD

Ulcerative colitis and Crohn's disease are chronic diseases of unknown etiology that are characterized by recurrent inflammation and ulcerations of intestinal or colonic mucosa and inappropriate healing .96 The present basic therapy for IBD relies on classic anti-inflammatory and immunosuppressive drugs, such as glucocorticoids, mesalamine derivatives, azathioprine, and derivatives of the latter that vary in their ability to induce and maintain control of symptoms as well as in their tolerability and toxicities Great progress has been made over the last decade in the development of targeted specific therapies for IBD, e.g ., antibodies against TNF-a (infliximab) and

Biological functions of 15lipoxygenases

The formation 15-H(P)ETE or 13-H(P)ODE is often elevated in inflamed tissue and it was believed for a long time that these compounds may exhibit proinflammatory activities. However, new experimental data suggested that 15-LOX products may act as anti-inflammatory agents. According to a newly developed concept, the in vivo activity of the 15-LOX may be regarded as a protective response to limit or reverse inflammatory symptoms and to maintain basic cell functions 209 ,

Efficacy and Toxicity

Eral experimental conditions, using only few experimental animals. The most promising compounds can then be studied in vivo. In addition to using individual cell cultures, the method of precision-cut liver slices seems to be an excellent procedure for the rapid testing of liver targeting preparations. The effect of anti-inflammatory targeting preparations can be studied in liver slices by the inhibition of mediator release after activation of resident cells with LPS. Dexa10-HSA, for instance, was shown to inhibit LPS-induced TNFa release more effectively than an equimolar quantity of free dexamethasone 152 . Another method is to study the effects on LPS-induced cell activation in a liver perfusion set-up system. Isolated perfused livers of rats pretreated with Corynebacterium parvum and subsequently challenged with LPS are a well-established model for hepatic inflammation. LPS-induced cholestasis and hepatic damage in this model were successfully prevented by the administration of...

Current Status Of Antiinfective And Immunemodifying Therapy In

Intracellular antiviral pathways.37 While 'active' intracellular bacterial infections, e.g. Lyme disease and tuberculosis, can certainly cause chronic fatigue as one of the common symptoms of systemic infections (secondary or symptomatic CFS), the patient with an active bacterial infection does not have CFS by definition, since a confident diagnosis of CFS can only be made after exclusion of all systemic medical causes (Table 15.2). However, unlike antiviral therapy in CFS (although newer antivirals such as pleconaril have not been tested), there has been anecdotal evidence of improvement in a small proportion of CFS patients treated with specific macrolide antibiotics (typically doxycycline, erythromycin or clarithromycin). During the outbreaks of neuromyasthenia in the 1960s, chloram-phenicol, another macrolide antibiotic, was believed to be effective in some patients.38 We do not yet know if this antibiotic-responsive CFS population represents a true cohort of 'chronically'...

Carboxylic and sulphonic acid groups

The introduction of carboxylic acid groups into small lead molecules may produce analogues that have a very different type of activity or are inactive. For example, the introduction of a carboxylic acid group into phenol results in the activity of the compound changing from being a toxic antiseptic to the less toxic anti-inflammatory salicylic acid. Similarly, the incorporation of a carboxylic acid group into the sympathomimetic phenylethylamine gives phenylalanine, which has no sympathomimetic activity. However, the introduction of carboxylic acid groups appears to have less effect on the activity of large molecules.

Renal Pathology and the Proximal Tubular Cell for Therapeutic Intervention

Targeting of anti-inflammatory and anti-fibrotic drugs to the proximal tubular cell may prevent tubulointerstitial inflammation and scarring secondary to systemic and glomerular infection and proteinuria. Furthermore, tubular drug delivery may be beneficial during shock, renal transplantation, ureter obstruction, diabetes, proteinuria, renal carcinoma and some tubular defect diseases such as Fanconi and Bartter's syndrome.

Experimental approaches

Several therapeutic agents which may limit meningeal inflammation have shown beneficial effects in animal models of bacterial meningitis (in particular of the rat and the rabbit). Aside from dexamethasone, these anti-inflammatory agents include non-steroidal anti-inflammatory drugs (e.g., indomethacin), pentoxifylline, antagonists of leukocyte-endothelial cell adhesion molecules, monoclonal antibodies against cytokines, platelet-activating factor receptor antagonists, free radical scavengers and NOS inhibitors. Apart from dexa-methasone, these agents have not yet been investigated in humans with bacterial meningitis, but some show promising beneficial effects in experimental models. Further experimental studies are needed to clarify whether some of these approaches may be applied to clinical practice.

Additional physiological properties of flavonoids

During the past five years, numerous research groups have reported on the biological effects of cocoa, and its flavanol and oligomer components. As is discussed above, it has been reported that in vitro, cocoa, and isolated cocoa flavanols and their oligomers, have the ability to increase the antioxidant capacity of solutions and slow the oxidation of LDL and liposomes 9-11 . While the ability of flavonoids to inhibit oxidative damage may explain some of their health benefits, it is important to recognize the fact that they can have numerous other effects. For example, in in vitro models, they have been shown to induce endothelium dependent vessel relaxation (EDR) 26 reduce the production of inflammatory cytokines, while increasing the production of anti-inflammatory cytokines 29,30 increase the synthesis of the antithrombotic lipid prostacyclin, while reducing the production of the proinflammatory cysteinyl leukotrienes 31 protect against peroxynitrite-dependent oxidation and...

Human Immunodeficiency Virus Infection

Cytokines promotes the depletion of intracellular GSH levels and secretion of TRX. Moreover, immunocompromised HIV-infected individuals (AIDS patients) with elevated plasma TRX levels die more quickly than those with normal plasma TRX levels 52 . Anti-inflammatory effects of circulating TRX may worsen the prognosis of such immunocompromised hosts. The possible roles of TRX in HIV infection are schematically shown in Figure 7. In vitro studies have shown that truncated TRX promotes the viral replication of HIV and the full length of TRX inhibits the viral replication and viral entry into CD4+ T cells, suggesting the possibility of clinical application of TRX for AIDS therapy.

Renal Delivery of Naproxen Lysozyme

Targeting of nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen could be of interest for the treatment of proteinuria and tubular defects such as Fanconi syndrome and Bartter's syndrome 73,74 . Although a conjugate with an ester spacer is preferred to a conjugate with a direct peptide linkage 66,67 , we continued our research using naproxen di

Definition Of Chemoprevention

Chemoprevention is defined as the use of natural or synthetic agents for the reversal of carcinogenesis. In their review of the subject, Gwyn and Sinicrope6 discuss epidemiologic studies that have consistently shown that the chronic intake of a nonsteroidal anti-inflammatory drug (NSAID), principally aspirin, can successfully reduce the incidence of colorectal adenomas and possibly CRCs. They note that NSAIDs such as cyclooxygenase-2 inhibitors celecoxib and sulindac, in addition to other varieties of chemopreventive agents, are being studied in patients at increased genetic risk of CRC, as well as those with sporadic colonic adenomas.

Preparation and effect of HfPS1 in SD rats

The abuse of ethanol is associated with detrimental effects on several bodily organs and is one of several factors causing gastrointestinal disorders. For the treatment of gastrointestinal symptoms such as ulcerative hemorrhages and perforations, many pharmaceutical products (e.g., non-steroidal anti-inflammatory drugs, NSAIDs) have been developed (Higham et al., 2002). However, NSAID group presents many important medical problems relating to their expense and side effects, despite recent pharmaceutical advances that have generally improved their therapeutic effects. Therefore, many researchers are investigating the natural materials that have pharmaceutical effects with fewer side effects. Among these natural materials, seaweed compounds, many of which are polysacchar-ides, have been studied for their various pharmaceutical effects and diverse biological activities. Sulfated galactans from the red marine alga Champia feldmannii show acute anti-inflammation, anticoagulation, and...

Pharmacologic Management of Myofascial Pain and Dysfunction

Summary This article on the pharmacologic management of myofascial pain and dysfunction is from an issue of Oral and Maxillofacial Clinics on the medical management of temporomandibular disorders (TMD). The authors discuss the most frequently used classes of drugs, providing information about their mechanism of action, indications and contraindications, methods of use, and possible adverse side effects. Specific drugs discussed include anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs, and corticosteroids muscle relaxants (other than benzodiazepines) antianxiety medications antidepressant medication opiate narcotic analgesics and local anesthetics. A final section covers the placebo effect. The author emphasizes the importance of understanding the patient in terms of compliance and tolerance of side effects in order to achieve successful management with pharmacologic therapy. 2 figures. 6 tables. 25 references. (AA-M).

Flavonoids and Chronic Disease

Research with cell cultures and animal models suggests flavonoids may play a role in promoting human health and reducing the risk of some chronic diseases. Flavonoids have been purported to have a beneficial effect on cardiovascular disease, cancer, neurodegenerative diseases, diabetes, and osteoporosis as well as having antibacterial, anticarcinogenic, antiinflammatory, diuretic, and immunostimulatory actions. Observational studies have associated

Cyclooxygenase expression in renal inflammation

The functional role of COX upregulation in different disease states remains to be determined. Upregulation of COX isoforms does not necessarily result in enhanced prostanoid synthesis because arachidonic acid, the substrate for both isoforms, may be limiting. Furthermore, due to the distinct localization of the enzymes it is not yet known whether upregulation of COX-2 and COX-1, respectively, leads to the same spectrum of prostanoids, which is dependent on the cell-specific expression of the downstream metabolizing enzymes. Finally it is an open question whether the enhanced levels of prostanoids have to be considered as pro- or anti-inflammatory.

Gastrointestinal Effects

Aspirin-induced gastric bleeding sometimes is painless, and if unrecognized may lead to iron-deficiency anemia (see Chapter 53). The daily ingestion of anti-inflammatory doses of aspirin (4 or 5 g) results in an average fecal blood loss of 3-8 mL day, as compared with 0.6 mL day in untreated subjects. Gastroscopic examination of aspirin-treated subjects often reveals discrete ulcerative and hemorrhagic lesions of the gastric mucosa in many cases, multiple hemorrhagic lesions with sharply demarcated areas of focal necrosis are observed.

The Therapeutic Problem

However, they become progressively less effective because, with increasing physical occlusion, they are unable to create open airways. A waning response to bronchodilator treatment is, therefore, a prime indicator of worsening asthma and of the need for anti-inflammatory steroid treatment. These relationships are illustrated in Figure 1, which is considerably based on Hume and Gandevia's observations (1).

Common Adverse Effects And Precautions

Tolmetin and ketorolac are structurally related heteroaryl acetic acid derivatives with different pharmacological features. Diclofenac is a phenylacetic acid derivative that was developed specifically as an anti-inflammatory agent. Tolmetin is an anti-inflammatory, analgesic, and antipyretic agent that, in recommended doses (200-600 mg three times a day), appears to be approximately equivalent in efficacy to moderate doses of aspirin. Tolmetin possesses typical tNSAID properties and side effects.

Acetylation of Cyclooxygenases and Traditional NSAIDs

Aspirin modifies the activity of both COX-1 and COX-2 by acetylation. In addition, COX splice variants (COX-1b (COX-3), COX-2a and others) have been detected with yet poorly defined biological relevance and susceptibility to acetylation by aspirin. Aspirin inhibits the recombinant human COX-1b, an effect not seen with acetaminophen 95 . COX-2 is the molecular target of aspirin for inhibition of inflammatory and immune responses. COX-2 is also involved in aspirin-related actions on cell proliferation and apoptosis (Sec-tion2.3.3). Prostaglandins, generated via both COX isoforms, contribute to inflammation and pain and both are inhibited by aspirin. However, inhibition of COX-2-dependent prostaglandin formation in vivo requires higher concentrations of aspirin and, in contrast to inhibition (acetylation) of platelet COX-1, is also sensitive to salicylates at about equal concentrations. An interesting suggestion by John Oates' group was that the inhibitory action of salicylate on COX-1...

The Pathophysiology of PD may Include Oxidative stress Inflammation andor Excitotoxicity

It has also been long been suspected that inflammation may play a role in the etiology of PD as well as other neurodegenerative diseases. Evidence includes an increase in microglial activation and an activation of the complement system see reviews 116,117-119 . Thus, it seems of considerable interest that 6-OHDA causes an inflammatory response in the SN 120,121 and that the anti-inflammatory drug minocycline as well as non-steroidal anti-inflammatory drugs (NSAID) can reduce 6-OHDA neurotoxicity (see review 116,122,123 ). Although some epidemiological evidence supports the concept of anti-inflammatory agents in the treatment of PD, a recent clinical pilot study has failed to find support for the use of minocycline in PD 124 . However, it is possible that this reflects a failure of the treatment to achieve a sufficient anti-inflammatory effect and or the necessity to provide treatment at an earlier stage of disease progression.

Cyclcooxygenase2 Selective Nsaids

The therapeutic use of the tNSAIDs has been limited by poor tolerability. Chronic users are prone to experience GI irritation in up to 20 of cases. However, the incidence of these adverse events had been falling sharply in the population prior to the introduction of the coxibs, perhaps reflecting a move away from use of high-dose aspirin as an anti-inflammatory drug strategy. Studies of the immediate early genes induced by inflammation led to the discovery of a gene with significant homology to the original COX enzyme, now designated COX-2. Because expression of this second COX enzyme was regulated by cytokines and mitogens, it was proposed to be the dominant source of prostaglandin formation in inflammation and cancer. It further was proposed that the original, constitutively expressed COX was the predominant source of cytoprotective prostaglandins formed by the gastrointestinal epithelium. Thus, selective inhibition of COX-2 was postulated to afford efficacy similar to tNSAIDs but...

Pharmacological Treatments

Recently, the focus of much of the research on pharmacotherapy has switched its focus from symptoms to disease progression. The range of drugs that have, in most cases, been tested in 6-OHDA models is too wide to be reviewed here, but includes (in alphabetical order) antioxidants, anti-inflammatory agents, calcium channel antagonists, creatine, DA agonists, glutamate antagonists, free radical scavengers, iron chelators, melatonin, MAO-B inhibitors, nitric oxide synthase inhibitors, and polyphenols see reviews 130,131 .

Pharmacotherapy Of Asthma

The pharmacotherapy of asthma employs drugs aimed at reducing airway inflammation (i.e., antiinflammatory agents) and drugs aimed more directly at decreasing bronchospasm (i.e., bron-chodilators). To these ends, six classes of therapeutic agents are presently indicated for asthma treatment b adrenergic receptor agonists, glucocorticoids, leukotriene inhibitors, chromones, methylxanthines, and inhibitors of immunoglobulin E (IgE).

Mechanism Of Glucocorticoid Action In Asthma

Glucocorticoids do not directly relax airway smooth muscle and thus have little effect on acute bronchoconstriction. Their anti-inflammatory effects in asthma include modulation of cytokine and chemokine production inhibition of eicosanoid synthesis marked inhibition of accumulation of basophils, eosinophils, and other leukocytes in lung tissue and decreased vascular permeability. Because of their profound and generalized anti-inflammatory actions, glucocorticoids are the most effective drugs used in the treatment of asthma.

Oxidative Stress Responses in Mammalian Cells

The HO-1 gene is one of the best studied models of redox regulation in higher organisms. HO-1 induction is believed to serve as an inducible defense pathway which removes heme liberated by oxygen. HO-1 protein and mRNA are strongly induced by ROS and other inducers of oxidative stress, including nitric oxide 60,82,172,173 . The sustained induction of HO-1 mRNA in conditions of oxidative stress and its induc-ibility in many tissues and different mammalian species has rendered HO-1 mRNA a useful marker of cellular oxidative stress at the mRNA level. In murine macrophages, HO-1 expression was shown to be induced by hydrogen peroxide via the transcription factor AP-1 8,24,25 . Activation of the mitogen-activated protein kinases (MAPKs), early-response kinase (ERK), and p38 was implicated in HO-1 expression in chicken hepatoma cells 43 . In view of the toxicity of ''free'' heme, HO-1 appears to be a redox-responsive product with protective activity against oxidative stress (reviewed in...

Potential Beneficial Effects of Marine Algal Sterols on Human Health

Has been well recognized due to their valuable health beneficial effects. Therefore, isolation and characterization of novel functional ingredients with biological activities from marine algae have gained much attention. Sterols are important structural component of cell membranes. It has been reported that plant sterols exhibit various beneficial biological activities such as hypercholester-olemic, antioxidant, anticancer, antidiabetic, antihypertensive, anti-inflammatory, antifungal, and antibacterial activities. Marine algae

Fluticasone Propionate

Topical anti-inflammatoryb 0.1 (cortisol acetate 1) Ratio Anti-inflammatory Oral 0.1 glucocorticoid products. In clinical trials it proved to be twice as active, on a weight basis, as BDP in asthmatic patients and to have less effect on HPA function (45). The exceptional anti-inflammatory activity of fluticasone propionate is a consequence of its persistent binding to the glucocorticoid receptor protein (46).

Nonpharmacologic Measures

Applications of cold (to reduce inflammation) or heat (to reduce spasms) to muscles or joints are commonly employed techniques but evidence for an analgesic benefit is mixed. Hypnosis has been shown to reduce pain associated with medical procedures however, it requires specific training and time to administer. Transcutaneous electrical nerve stimulation (TENS) has shown conflicting results in terms of an analgesic benefit in the acute setting, but it has been shown to reduce the need for pharmacologic analgesics. There is limited evidence of benefit in the acute setting from relaxation and guided imagery. Acupuncture and electro-acupuncture have been shown to be of benefit in the acute setting both to improve pain and to reduce common opioid side effects however, they require specific training and time to administer.

Endogenous Protective Mechanisms

Not all mediators induced in the ischemic penumbra necessarily contribute to cellular death. Thus, protective compounds such as the heat shock proteins,10,92 anti-inflammatory cytokines70,78 and growth fac-tors93-99 are all induced in the early hours following ischemia (Table 22.2). These mediators possess anti-ischemic properties and represent endogenous efforts to counteract ischemic damage and improve neuronal repair. Unfortunately, the secretion of such survival-promoting agents is limited both in time and space and usually cannot completely counteract the overwhelming death-promoting processes mentioned above. Anti-inflammatory cytokines (e.g. IL-10) Antioxidants (glutathione)

Actions of Salicylates on Transcription Factors At

The time, it was not known that human vascular endothelial cells express the inducible COX-2 isoform after stimulation by cytokines. Later work suggested that salicylate, after entering the cell, interacts with the CCAT enhancer-binding protein-b (C EBP-b) in the nucleus, prevents the binding of this transcription factor, and downregulates COX-2 gene expression. This effect is seen at therapeutic analgesic anti-inflammatory concentrations (0.01-< 1mM) of the compounds. At higher concentrations (> 1 mM) salicylates additionally inhibit the binding of additional transcription factors, such as nuclear factor kB (NFkB) 135 . These effects of salicylates are not limited to COX-2 but are also seen with inducible NO synthase (iNOS) and probably many other genes that are regulated by the same transcription factors in their promoter region. This issue is discussed in more detail in Section 2.2.2. Similar to salicylates, naproxen was also found to transcriptionally downregulate COX-2 (and...

Transrepression Mechanisms

Very recently, a novel mechanism, corepressor interference, by which PPARy could exert its anti-inflammatory activity, was proposed. NFkB-regulated inflammatory genes are maintained in a repressed state through their association with nuclear corepressor (NCoR) complexes and upon exposure to proinflammatory stimuli this complex is dissociated and gene expression initiated. Glass and colleagues reported that the PPARy ligand-binding domain is sumoylated upon ligand-binding. This modified receptor then binds to NCoR containing complexes that are resident on the promoters of NF B-regulated genes. This interaction prevents the dismissal of the corepressor complex and thus suppresses NF B-dependent inflammatory gene expression 14 .

Neuroprotection In Ischemia

Studies employing antioxidants for cerebral protection have also yielded promising results in laboratory animals but have failed to produce clinically significant improvements in humans.108-110 Likewise, studies employing anti-inflammatory agents showed very promising results in laboratory animals but very disappointing results in clinical practice, including a study that reported excess mortality in patients treated with a monoclonal anti-ICAM antibody.12,67,70,72,111-113 Furthermore, it has been repeatedly shown that apoptotic death can be prevented by manipulations of the steps that lead to activation of the caspase cascade or by direct inhibition of caspases.86,114-116 However, no clinical data regarding the efficacy of such agents in humans are currently available. Endothelin antagonists have also been shown to reduce ischemic damage in animal models, probably by improving perfusion to the ischemic zone.117,118 However, no clinical human data on the use of these agents are...

Recent Concern About Inhaled b2Adrenoceptor Agonists

According to these guidelines, less severe chronic asthma should be treated with regular inhalations of an anti-inflammatory steroid supplemented when necessary by occasional inhalations of a short-acting b2-agonist such as salbutamol. Regular inhalations of a long-acting b2-agonist are reserved for patients with more severe disease that is still inadequately controlled after the dose of steroid is increased. These recommendations are clearly inconsistent in that regular b2-agonist inhalations are avoided for fear of worsening less severe asthma and yet are expected to ameliorate more severe disease. Surprisingly, this general approach to therapy is maintained in revised BTS guidelines issued in 1997 (52b). The only significant change is that concurrent salmeterol and low-dose steroid treatment is allowed as an alternative to increasing the inhaled steroid intake.

Further Actions of Salicylates on Arachidonate Metabolism

Arachidonic Acid Release Daily intake of aspirin at oral doses of > 3 g reduces incorporation of arachi-donic acid into isolated mononuclear cells by about 50 . Similar effects are seen after incubation of white cells with 0.3 mg ml aspirin in vitro 137 . This suggests that aspirin at anti-inflammatory concentrations might modify the generation of arachidonic acid metabolites via alteration of the fatty acid composition of membrane phospholipids. An inhibition of arachidonic acid release by higher con-

Autonomic Nervous System

In addition to immune regulation by the sympathetic branch, the parasympathetic branch of the ANS has been shown to contribute to the regulation of innate immune responses via an efferent neural signaling pathway referred to as the cholinergic anti-inflammatory pathway (Tracey 2002). The existence of this pathway was initially identified in studies showing that stimulation of the vagus nerve attenuates immune system activation and the physiological signs of septic shock in response to lipopolysaccharide, a key component of gram-negative bacterial cell walls (Borovikova et al. 2000). Follow-up studies have determined that vagal release of acetylcholine, which in turn interacts with the k7 subunit of the nicotinic AChR (u7 nAChR) on relevant immune cells, is capable of suppressing production of cytokines, including TNF-ct, via inhibitory effects on nuclear translocation of NF-kB (Altavilla et al. 2006 Guarini et al. 2003) and activation of Janus kinase (JAK) 2 signal transducers and...

Glucocorticoid Receptor

The main strategy towards pharmacological modulation of the GCR, over many years, has been the development of steroidal receptor agonists, with varying potencies, for use as anti-inflammatory drugs 4 . Recently, this search has been focused on the dissociation of anti-inflammatory actions from metabolic side effects. In contrast, despite intensive research, the only glucocorticoid receptor antagonist that is available for clinical use is the steroid, mifepristone (RU486).

Role Of Mitogenactivated Protein Kinase In Stroke And Cns Injury

MEKl-specific antagonist, PD98059, significantly protected from focal cerebral ischemic injury.67 Stress-activated protein kinases (e.g. SAPKs and p38 MAPK) play an essential role in cells' responses to cytokines and various environmental stimuli. Recently, a new class of compounds, cytokine-suppressive anti-inflammatory drugs (CSAIDs), potent inhibitors of TNF-a and IL-1p production, have been developed.68 Targeting p38 MAPK may provide an opportunity not only for intervention in early cytokine production but also to block delayed neuronal death by apoptosis after ischemic injury. Very recently, the selective p38 MAPK inhibitor was demonstrated to reduce ischemic infarct (up to 40 ) and neurological deficits (35 ) in a rat model of focal brain ischemia, supporting the importance of p38 MAPK in focal ischemia-induced brain injury.69

Bioactions of lipoxins

LXs are generated in vivo during the resolution phase of an inflammatory response. This is a rapid process that is activated by pro-inflammatory components such as IL-4, IL-13 or granulocyte-macrophage colony-stimulating factor (GM-CSF) through increases in LO activity (Levy et al. 2001). The role for LXs as anti-inflammatory molecules is well defined, with bioactions involving the inhibition of chemotactic responses of PMN and stimulating the activation of monocytes and macrophages (Serhan 2002). In conjunction with their anti-inflammatory bioactions, there is a growing appreciation that LX biosynthesis coincides with the resolution phase of inflammation, and so mediates numerous pro-resolution effects such as stimulation of macrophage clearance of apoptotic PMN from an inflammatory focus, modulation of cytokine-stimulated metalloproteinase activity and inhibition of cellular proliferation (Fig. 1) (McMahon et al. 2001). Most recently, we have developed an in vitro model of renal...

Glucocorticoids NSAIDs and Others

Glucocorticoids are commonly used in inflammatory disorders owing to their broad anti-inflammatory and immune suppressive effects in a wide variety of diseases. A major drawback of these compounds is the serious side-effects associated with their use. They have at least a partial inhibitory effect on the expression of adhesion molecules by the endothelium and inhibit cytokine production 2 . For instance, the glucocorticoid dexamethasone impaired the increase of E-selectin and ICAM-1 expression on HUVEC, at least partially by an inhibitory effect on NFkB (Figure 7.4) 100-102 . In IBD patients, prednisolone, another glucocorticoid, blocked NFkB activation thereby inducing healing of colonic inflammation 103 . Barnes and Karin also underlined the beneficial effect of glucocorticoids in chronic inflammatory diseases via NFKB-mediated mechanisms 90 . The anti-angiogenic effects of glucocorticoids were demonstrated by the ability of dexamethasone to inhibit capillary Non-steroidal...

Pharmacological Inhibition Of Cytokines Is Protective In Brain Injury

TNF-a production is regulated at both transcriptional and translational levels, so a TNF-a mRNA inhibitor such as rolipram (a phosphodiesterase inhibitor) or tyrphostins, which inhibit protein tyrosine kinases, could be used to treat TNF-a-mediated diseases.21,22 CNI-1493, a tetravalent guanylhydrazone compound that inhibits phosphorylation of p38 mitogen-activated protein (MAP) kinase, has been shown to selectively inhibit TNF-a synthesis.23,24 This drug, used in cerebral ischemia25 and trauma (unpublished observations from our laboratory), gave significant cerebroprotection. In our model of closed head injury, we inhibited TNF-a translation (dexanabi-nol),18 expression (pentoxyphylline), and activity (TNF-a-binding protein)26 and demonstrated neuroprotection. Namely, less edema formation and blood-brain barrier disruption were found, along with faster and greater clinical recovery. In addition, the anti-inflammatory cytokine interleukin-10 (IL-10) was used in a model of traumatic...

Transcription factors involved in lipoxin A4 signalling

As previously discussed, LX signalling via a G-protein-coupled receptor is thought to be partly regulated at the transcription level, but it may also govern the regulation of other genes associated with the resolution of inflammation. Indeed, many complementary oligonucleotide microarray and bioinformatics analyses have indicated numerous anti-inflammatory, pro-resolution and, more recently, pro-fibrotic genes modified by LXA4 in various disease settings (Gewirtz et al. 2002 Kieran et al. 2003 Leonard et al. 2002 Rodgers et al. 2005). Given that transcription is dependent on a plethora of transcription factors, co-activators and co-repressors, it is quite difficult to assign a direct LX-dependent effect that might be involved in the modulation of the above genes. However, several publications have suggested the involvement of NF-kB, AP-1, Sp-1 and the co-repressor NAB 1. In an attempt to elucidate a mechanism by which LXs, ATL and their stable synthetic analogues exert their...

Tnf Deficiency Is Deleterious In Brain Injury

In a study on the recovery of TNF(- -) mice after traumatic injury, Scherbel et al proposed a solution to the apparent conflict concerning the role of TNF-a after trauma.34 They showed that during the first post-trauma days (up to 4 days), the clinical status of the TNF(- -) mice was better than that of their matched controls, as expected from the pharmacological studies. However, their motor function did not improve from day 1 on, whereas the wild-type mice, who failed in most clinical tests on days 1-4, started to regain function and, by day 7, they performed better in the motor testing, with further improvement up to day 14. A similar biphasic effect was also found when histological changes were analyzed. Support for this notion of the dual, time-dependent role of TNF-a after trauma came from Bethea et al, who studied the effect of TNF-a inhibition on recovery after spinal cord injury. As mentioned above, they treated rats after spinal cord injury with IL-10, an anti-inflammatory...

Immune System Interventions for Behavioral Symptoms

Given that proinflammatory cytokines induce depressive syndromes, and given that many medically healthy patients with depression appear to demonstrate increased inflammatory activity, it is logical to inquire as to whether agents that directly target inflammatory mediators, such as anti-inflammatory agents and drugs that disrupt cytokines and their cytokine signaling pathways (e.g., NF-kB, p38 MAPK), might be of benefit in the treatment of both stress- and immune-related neurobehavioral disorders. Indeed, in a recent double-blind, randomized, placebo-controlled study, patients with major depressive disorder who took celecoxib as an adjunct to reboxetine experienced a significantly greater therapeutic benefit than those taking reboxetine alone (M ller et al. 2006). In animal models, endogenous inhibitors of proinflammatory cytokines, such as the soluble receptor antagonist for IL-1 (sIL-1ra), have been reported to attenuate or abolish sickness symptoms following endotoxin or cytokine...

Opioids and Adjuvants

In the acute setting, frequent small doses of intravenous opioids may be used. Hydromorphone, morphine, and fentanyl are all acceptable choices, while meperidine should be avoided because of the potential accumulation of active metabolites and reduction in seizure threshold. Individual patients will have different opioid requirements so doses must be carefully titrated to effect in order to achieve analgesia. Trauma is more likely to occur in young males, individuals with psychiatric disorders, and those with substance abuse problems. Although these patients often require high doses of opioids, and are at increased risk for addiction and aberrant behaviors, there is a clear consensus that these concerns should not affect the short-term goal of adequate pain control (Bourne et al. 2008). In patients who receive parenteral opioids, there is strong evidence that the use of PCA is associated with better pain relief and less side effects than PRN administration. Specific issues that may...

Metabolism of Polyunsaturated Fatty Acids and its Effect on Neural Membranes Receptors

In neural membranes DHA mainly incorporates in ethanolamine plasmalogen (PlsEtn) and phosphatidylserine (PtdSer), whereas majority of ARA incorporates into phosphatidylcholine (PtdCho). From PlsEtn and PtdSer, DHA is released by the action of plasmalogen-selective PLA2 and PtdSer hydrolyzing PLA2, respectively 12-15 . The released DHA is metabolized into resolvins and neuroprotectins by 15-lipoxygenase 16-18 . These mediators are collectively known as docosanoids. They have anti-inflammatory and antiapoptotic properties and are involved in neuroprotection. In addition, docosanoids have antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory effects 4,16-18 . In contrast, ARA is released from neural membrane PtdCho by cPLA2 and metabolized to prostaglandins, leukotrienes and thromboxanes. These metabolites are collectively known as eicosanoids. These metabolites have prothrombotic, proaggregatory, and proinflammatory properties. The levels of eicosanoids and docosanoids in...

Inflammatory Bowel Disease

There is a wide variety of animal models that mimic aspects of inflammatory bowel disease. The choice of an appropriate model depends on the question being addressed in a particular study. There are multiple factors contributing to IBD, including for example, environmental or genetic susceptibility. Common experimental models differ largely with regard to the factors that contribute most prominently to the pathogenesis of IBD. Therefore not only should the model be chosen carefully, but the intrinsic limitations in the interpretation of results should also be recognized. For instance, to test new anti-inflammatory drugs a simple and reproducible model involving non-specific inflammation might be selected. Examples are dex-tran sodium sulphate (DSS)-induced colitis in which the cellular toxicity of DSS induces an inflammatory reaction, or trinitrobenzene sulfonic acid (TNBS)-induced colitis, which is a delayed-type hypersensitivity response to this contact allergen. In addition to...

Design of Heteroaromatic Lipoxin A4 Analogues

In this context, we have designed a synthesis which allows us to replace the stable benzene moiety with five- and six-membered heterocycles such as thiophene and pyridine, respectively. Finally we attempted the synthesis of furan- and indole-con-taining LXA4 analogues. These analogues will assist in our ongoing efforts to prepare and evaluate novel bioactive LXA4 analogues with anti-inflammatory effects.

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